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- Title
GPR119: a promising target for nonalcoholic fatty liver disease.
- Authors
Jin Won Yang; Hyo Seon Kim; Ji Hye Im; Ji Won Kim; Dae Won Jun; Sung Chul Lim; Kyeong Lee; Jong Min Choi; Sang Kyum Kim; Keon Wook Kang
- Abstract
Nonalcoholic fatty liver disease is associated with metabolic syndrome and has the unique characteristic of excess lipid accumulation in liver. G-protein-coupled receptor 119 (GPR119) is a promising target for type 2 diabetes. However, the role of GPR119 activation in hepatic steatosis and its precise mechanism has not been investigated. In primary cultured hepatocytes from wild-type and GPR119 knockout (KO) mice, expression of lipogenic enzymes was elevated in GPR119 KO hepatocytes. Treatment of hepatocytes and HepG2 cells with GPR119 agonists in phase 2 clinical trials (MBX-2982 [MBX] and GSK1292263) inhibited protein expression of both nuclear and total sterol regulatory element binding protein (SREBP)-1, a key lipogenesis transcription factor. Oral administration of MBX in mice fed a high-fat diet potently inhibited hepatic lipid accumulation and expression levels of SREBP-1 and lipogenesis-related genes, whereas the hepatic antilipogenesis effects of MBX were abolished in GPR119 KO mice. MBX activated AMPK and increased Ser-372 phosphorylation of SREBP-1c, an inhibitory form of SREBP-1c. Moreover, inhibition of AMPK recovered MBX-induced down-regulation of SREBP-1. These findings demonstrate for the first time that the GPR119 ligand alleviates hepatic steatosis by inhibiting SREBP-1-mediated lipogenesis in hepatocytes.--Yang, J. W., Kim, H. S., Im, J. H., Kim, J. W., Jun, D. W., Lim, S. C., Lee, K., Choi, J. M., Kim, S. K., Kang, K. W. GPR119: a promising target for nonalcoholic fatty liver disease.
- Subjects
FATTY liver; THERAPEUTICS; G protein coupled receptors; LIPID synthesis; PROTEIN expression; TYPE 2 diabetes; HIGH-fat diet; ADENOSINE monophosphate
- Publication
FASEB Journal, 2016, Vol 30, Issue 1, p324
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.15-273771